U.S. Pat. No. 4,831,031 discloses that arylpiperazinyl-ethyl (or butyl)-heterocyclic compounds of formula (I) may be prepared by reacting piperazines of the formula (II) with compounds of the formula (III) in a polar organic solvent; in the presence of a tertiary amine base or alkali metal base, and in the further presence of catalytic amount of sodium iodide. The final product is purified by chromatography.
Ziprasidone covered in '031 is synthesized by the coupling reaction of 3-piperazinylbenzo[d]isothiazole and 6-chloro-5-(2-chloroethyl)indolin-2-one.
The abovementioned method suffers from the following disadvantages,    1) Longer reaction time of 24 to 72 hours,    2) Formation of considerable quantities of by products,    3) Environmental burden of handling and disposal of aqueous and non aqueous effluents,    4) Special purification techniques like chromatography and,    5) Variable yields ranging from 14 to 84%.
U.S. Pat. No. 5,206,366 discloses a process for making (I), in particular Ziprasidone, by reacting equimolar amounts of (II) and (III) in water and in the presence of a neutralizing agent such as Na2CO3, at refluxing temperature for about 9 to 12 hours.
Further U.S. Pat. No. 5,338,846 discloses a process for the preparation of hydrochloride salt of (I), in particular Ziprasidone, by refluxing an equimolar mixture of hydrochloride salt of (II) with (III) in water and in presence of a neutralizing agent Na2CO3 for about 8 to 16 hours.
The methods disclosed in '366 and '846 uses large excess of neutralizing agent and water resulting in voluminous reaction mixture and chances of residual carbonate impurities in the final product.
Surprisingly, we have found that the above coupling reaction to manufacture (I) could be achieved by mixing (II) and (III) and heating to an appropriate temperature without the use of any solvent or optionally as a suspension in a minimum quantity of a non-aqueous suspending liquid in the presence of a neutralizing agent and catalytic amount of alkali metal halide. The reaction occurs in the fused state by the melting of one of the reactants and the resulting suspension will facilitate proper mixing and better heat transfer.
The process of present invention thus dispenses with the need for using large amounts of solvents for the coupling process as in the prior-art methods.